Expression of phosphorylated p21-activated kinase 4 is associated with aggressive histologic characteristics and poor prognosis in patients with surgically treated renal cell carcinoma

Investig Clin Urol. 2021 Jul;62(4):399-407. doi: 10.4111/icu.20200399. Epub 2021 May 17.

Abstract

Purpose: P21-activated kinase 4 (PAK4), a serine/threonine kinase that regulates a number of fundamental cellular processes, has been suggested as a prognostic factor for various human tumors. The aim of the present study was to evaluate the clinical implications of phospho-Ser474 PAK4 (pPAK4S474), an activated form of PAK4, in surgically treated renal cell carcinoma (RCC).

Materials and methods: Samples from 131 patients with surgically treated RCC were immunostained to detect PAK4 and pPAK4S474. Expression of PAK4 and pPAK4S474 was compared with clinicopathological characteristics and survival after nephrectomy.

Results: PAK4 and pPAK4S474 were expressed predominantly in the nucleus. Overall, 57.3% (75/131) and 24.4% (29/119) of specimens exhibited high expression of pPAK4S474 and PAK4, respectively. High expression of pPAK4S474 was associated with adverse pathologic characteristics, including advanced tumor stage and grade (p=0.036 and p=0.002, respectively), whereas this association was not significant for PAK4 expression (each p>0.05). Kaplan-Meier estimates showed that high expression of pPAK4S474 was associated with shorter recurrence-free survival in a subgroup with localized RCC and with cancer-specific survival in the total RCC cohort (log-rank test: p=0.001 and p=0.005, respectively), whereas PAK4 expression was not. Multivariate Cox regression analysis identified that high pPAK4S474 expression was an independent predictor of recurrence in the subgroup with localized RCC.

Conclusions: pPAK4S474 may be a more accurate prognostic factor than total PAK4 in RCC patients. This marker would be useful for identifying patients with pathologically localized disease who may require further interventions.

Keywords: P21-activated kinase 4; Recurrence; Renal cell carcinoma; Survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology*
  • Carcinoma, Renal Cell / surgery
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology*
  • Kidney Neoplasms / surgery
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Staging
  • Phosphorylation
  • Prognosis
  • Proportional Hazards Models
  • Survival Rate
  • p21-Activated Kinases / metabolism*

Substances

  • PAK4 protein, human
  • p21-Activated Kinases